The overall aim of this proposal is to further evaluate, in non-human primates, the neurophysiologic, therapeutic and potential neuroprotective effects of inactivation of the subthalamic nucleus (STN) for Parkinson's disease (PD). Over the past five years pallidotomy, and more recently, deep brain stimulation (DBS) of the STN and the internal segment of the globus pallidus (GPi), have been increasingly employed in the treatment of advanced, medicaLly intractable PD. Based on the current pathophysiological model of PD, increased excitatory derive from the subthalamic nucleus (STN) on GPi neurons leads to increased (inhibitory) output from GPi and excessive inhibition of thalamocortical neurons. This is believed to be responsible for the hypokinetic features of PD. The improvement in motor symptoms following STN lesioning is postulated to occur, in large part, as a result of increased thalamocortical activity. There is, however, little direct evidence from electrophysiological recording within the thalamocortical circuit to support or refute this proposal. Similarly, the mechanism underlying the therapeutic effects of STN stimulation remains unclear, even through symptomatically DBS and ablation appear to have similar effects, suggesting that DBS acts to reduce output from the site of stimulation. Studies using STN stimulation and microdialysis and microdialysis in GPi will test the major hypotheses regarding the mechanism of action of DBS. In this proposal the physiological basis for the benefits from STN ablation and DBS will be investigated in the MPTP primate model of PD using a combination of single cell recording, imaging with PET and microdialysis. In addition to the therapeutic benefits of STN lesions on parkinsonian signs, lesions of the STN in rodents have been reported to provide a neuroprotective effect against 6-OH dopamine for neurons of the substantia nigra pars compacta (SNc). Whether STN ablation and stimulation are equally effective therapeutically, and whether they have a neuroprotective effect are key issues in the field of PD research. The potential therapeutic and neuroprotective roles of inactivation of the STN may also be critically important to the future treatment of patients with idiopathic PD. The latter may lead to consideration of surgical intervention or pharmacologic blockade of glutamate receptors earlier in the course of the disease to prevent further destruction of SNc neurons and the progressive worsening of parkinsonian motor signs.